PROJECT SUMMARY/ABSTRACT Takotsubo syndrome (TS) is an increasingly recognized condition characterized by acute, reversible systolic heart failure which uniquely affects older women (more than 90% of cases). Although most patients recover after an acute episode, survivors have a high risk of long-term major cerebrovascular events (MACCE) and of chronic impairments of the left ventricular (LV) function. Despite its clinical relevance, important knowledge gaps exist about this interesting and perhaps underappreciated condition. While there is a general consensus that an exaggerated sympathetic nervous system (SNS) discharge is the final common pathophysiologic event that underlies the onset of acute systolic heart failure in TS, this condition has considerable heterogeneity. First, exposure to an emotional trigger was thought to be a defining precipitant of TS, but recent registry data indicate instead that emotional triggers are present only in 1/3 of cases, with physical triggers (1/3) and no triggers (1/3) accounting for the remaining cases. Second, the pathophysiological pathway linking the precipitating trigger to the onset of TS remains to be articulated. Third, it is unclear why certain individuals develop an exaggerated SNS response when exposed to emotional triggers which sooner or later affect all individuals throughout the lifespan with no or limited health consequences. Finally, no study has rigorously tested the contribution of triggering event and mental stress responsiveness to the long-term prognosis of these patients. To address these key evidence gaps we will conduct a mechanistic clinical trial among 246 newly admitted patients with a validated diagnosis of TS from 3 large medical centers in the Providence, RI area. Participants will undergo a comprehensive interview to identify the events proximal to the onset of TS and complete a battery of psychosocial questionnaires 2 weeks after hospital discharge. Approximately 4 weeks after discharge they will undergo a laboratory mental stress protocol previously utilized by our group. Baseline and reactive changes in measures of autonomic nervous system activity (circulating catecholamines and cardiac vagal control), LV function (2D speckle tracking echocardiography (2D-STE)), and hemodynamic parameters will be assessed. LV function and MACCE will be assessed 12 months later. The proposed study will address the noted evidence gaps by a) Rigorously assessing the full range of circumstances proximal to TS onset, b) Assessing the constellation of physiological elements that define TS (autonomic nervous system activity and LV function) under controlled conditions, and c) Link the type of trigger to physiology. Furthermore, by using 2D-STE we will be able to capture both reactive and long-term subtle anomalies of LV function in these patients. This will be the first study to rigorously investigate the heterogeneity in clinical presentation, physiopathology, and prognosis in TS. The identification of distinct sub-groups in TS will provide the rationale for the design and testing of properly targeted interventions to improve the prognosis of these patients.